We have shown that calcitonin gene-related peptide (CGRP) is released into the circulation during endotoxin or hemorrhagic shock. In the present study, it was observed that low pH, elevated levels of lactic acid, hypertonic NaCl and hypertonic sucrose caused CGRP release from isolated mesenteric arterial bed (MAB) of rat. All the responses were blocked when MAB was pretreated with capsaicin. Ruthenium red, an inhibitor of Ca(2+)-induced Ca2+ release from intracellular Ca2+ pools, significantly inhibited the release of CGRP. In Ca2+ free medium, low pH, lactic acid and hypertonic solutions became no longer capable of inducing the release of CGRP. The above results suggest that the observed release of CGRP in MAB was mediated by capsaicin-sensitive sensory nerve endings, as a result of Ca(2+)-induced Ca2+ release from the intracellular Ca2+ store which is sensitive to ruthenium red.